Therapeutic treatment of H. pylori associated gastroduodenal disease

ABSTRACT

The application discloses a method for the treatment of Heliobacter infection in a mammalian host, which comprises administration to said infected host of an immunologically effective amount of one or more Heliobacter antigen(s), optionally in association with a mucosal adjuvant.

This Application is a 371 of PCT/AU94/00416 filed Jul. 25, 1994, whichclaims foreign priority to Australian applications: PM3828, filed Feb.14, 1994 and PMO157 filed Jul. 27, 1993.

FIELD OF THE INVENTION

This invention relates to the treatment of gastroduodenal diseaseassociated with Helicobacter pylori infection and in particular itrelates to the use of active immunisation as a treatment for H.pylori-associated gastroduodenal disease.

BACKGROUND OF THE INVENTION

The bacterium, Helicobacter pylori, is now well established as a majorgastroduodenal pathogen, and more than 50% of the world population isinfected with this organism which causes gastritis of varying severity.While no symptoms are apparent in a great proportion of infectedpersons, in a significant number of H. pylori infected persons overtdisease may result. The majority (95%) of duodenal ulcers are associatedwith H. pylori infection; a causal role is shown by treatment studieswhich indicate that if the organisms can be eradicated at the time ofulcer healing then the ulcers do not recur--in contrast to 80%recurrence rate at one year in those who remain infected with theorganisms. Furthermore, up to 80% of gastric ulcers are thought to be H.pylori associated (Blaser, 1992).

There is now increasing evidence of the harmful consequence of long termH. pylori infection. In countries such as China, Colombia and Japan thebacterium is picked up very early in life, and in these persons thegastritis slowly progresses until after 30-40 years of continualinfection, severe gastric atrophy appears. Gastric atrophy is welldocumented as being the precursor lesion for gastric cancer, althoughthe actual cancer that develops in an atrophied stomach is dependent ona myriad of other factors including diet. However, all the evidence todate would suggest that the cancer would not develop if it was possibleto remove the H. pylori infection at an early age before the atrophy haddeveloped (Parsonnet et al., 1991).

There is no laboratory animal model of H. pylori infection that can beused for large scale assessment of new anti-H. pylori therapies.However, a Helicobacter felis mouse model of gastric Helicobacterinfection has been developed that has proved extremely useful in thescreening of the potential of new antimicrobial therapeutic regimens. H.felis is a spiral shaped bacterium that is very closely related to H.pylori. This bacterium colonises the stomach of mice in a very similarway to H. pylori in the human, i.e. the main ecological niche is gastricmucus and the localisation of colonisation is antral dominant. Ingermfree mice, H. felis infection induces a gastritis that is verysimilar to the human H. pylori infection with a chronic inflammationaccompanied by polymorphonuclear leucocyte infiltration. Infection witheach organism results in the induction of a similar raised immuneresponse against H. pylori and H. felis respectively (Lee et al., 1990).

The H. felis mouse model has proved to be very predictive of theefficacy of anti-H. pylori agents in humans. Thus, monotherapy withagents with high in vitro activity such as erythromycin show nosignificant in vivo effect against H. felis in mice, just aserythromycin has no anti-H. pylori effect in humans despite highantimicrobial effects in vitro. In contrast, the triple therapy regimensof a bismuth compound, metronidazole, and tetracycline or amoxycillinlead to a very high eradication rate in H. felis infected mice(Dick-Hegedus and Lee, 1991). Such triple therapies are the mostsuccessful human anti-H. pylori regimens, and at the present time arerecommended as the first choice for anti-H. pylori therapy. However,established Helicobacter infections are difficult to treat, and currentchemotherapeutic regimens remain suboptimal due to problems withefficacy, toxicity, drug resistance and reinfection (O'Connor, 1992).

Active immunisation of already infected patients has not been provenefficacious for any clinically manifest human infectious disease (Burke,1992). Given that H. pylori infections persist for long periods, if notthe life of the infected individual, despite the presence of a vigorousimmune response that includes a high level of circulating IgG antibodyin the serum and the demonstration of local specific IgA antibody in thegastric mucosa, it has been considered that active immunisation wasunlikely to be effective in therapy (Goodwin, 1993). Indeed, Czinn etal. (1993) in proposing that oral vaccination may be a feasible approachfor the prevention of H. pylori infection in humans (based on anevaluation of an oral immunisation protocol in the H. felis mousemodel), suggested that once infection is established neither antibodynor antibiotics are very effective at eradication.

Varga et al. (1992) have reported that a H. pylori vaccine prepared fromorganisms derived from a patient, and injected parenterally into thatpatient, resulted in an allergic reaction and failure to eradicate theorganism.

Surprisingly, it has now been discovered for the first time that thereis indeed a therapeutic potential for active immunisation againstgastric Helicobacter infection. Furthermore, it has been discovered thatoral administration of H. pylori antigen, with a suitable mucosaladjuvant, does not result in allergic or hypersensitivity symptoms, butresults in suppression or eradication of the infecting organisms fromthe gastric mucosa.

SUMMARY OF THE INVENTION

According to one aspect of the present invention, there is provided amethod for the treatment of Helicobacter infection in a mammalian host,which comprises the oral administration to said infected host of animmunologically effective amount of one or more Helicobacter antigen(s),optionally in association with a mucosal adjuvant.

In another aspect, there is provided a vaccine composition for thetreatment of Helicobacter infection in a mammalian host, which comprisesan immunologically effective amount of one or more Helicobacterantigen(s), optionally in association with a mucosal adjuvant.

In yet another aspect, the present invention provides the use of avaccine composition comprising an immunologically effective amount ofone or more Helicobacter antigen(s), optionally in association with amucosal adjuvant, in the treatment of Helicobacter infection in amammalian host.

Throughout this specification and the claims which follow, unless thecontext requires otherwise, the word "comprise", or variations such as"comprises" or "comprising", will be understood to imply the inclusionof a stated integer or group of integers but not the exclusion of anyother integer or group of integers.

By use of the term "immunologically effective amount" herein, it ismeant that the administration of that amount to an individual infectedhost, either in a single dose or as part of a series, is effective fortreatment of Helicobacter infection. This amount varies depending uponthe health and physical condition of the individual to be treated, thetaxonomic group of individual to be treated, the capacity of theindividual's immune system to synthesise antibodies, the degree ofprotection desired, the formulation of the vaccine, the assessment ofthe medical situation, and other relevant factors. It is expected thatthe amount will fall in a relatively broad range that can be determinedthrough routine trials.

DETAILED DESCRIPTION OF THE INVENTION

The Helicobacter antigen(s) used in accordance with the presentinvention may be H. felis antigen(s), or more preferably H. pyloriantigen(s). In a particularly preferred aspect of the present invention,a vaccine composition comprising H. pylori antigen(s) in associationwith a mucosal adjuvant is used in the treatment of H. pylori infectionin a human patient.

Preferably, the Helicobacter antigen(s) comprise a bacterial sonicate,and in particular a H. pylori sonicate. More preferably, theHelicobacter antigen(s) used in accordance with the present inventioncomprise inactivated whole bacterial cells of H. pylori.

Alternatively, the Helicobacter antigen(s) used in accordance with thepresent invention may comprise one or more individual antigens,particularly one or more H. pylori antigens such as H. pylori urease, orH. pylori cytotoxin (CT), Cytotoxin Associated Immunodominant (CAI)antigen or heat shock protein (hsp) as disclosed by way of example inInternational Patent Publication No. WO 93/18150.

One mucosal adjuvant which is optionally, and preferably, administeredwith the Helicobacter antigen(s) to the infected host is cholera toxin.Another preferred mucosal adjuvant which may be administered with theHelicobacter antigen(s) is E. coli heat labile toxin (E. coli HLT).Mucosal adjuvants other than cholera toxin and E. coli HLT which may beused in accordance with the present invention include non-toxicderivatives of cholera toxin, such as the B sub-unit (CTB), chemicallymodified cholera toxin, or related proteins produced by modification ofthe cholera toxin amino acid sequence. Each of these molecules withmucosal adjuvant or delivery properties may be added to, or conjugatedwith, the Helicobacter antigen(s). Other compounds with mucosal adjuvantor delivery activity may be used, such as: bile; polycations such asDEAE-dextran and polyornithine; detergents such as sodium dodecylbenzene sulphate; lipid-conjugated materials; antibiotics such asstreptomycin; vitamin A; and other compounds that alter the structuralor functional integrity of mucosal surfaces. Other mucosally activecompounds include derivatives of microbial structures such as MDP;acridine and cimetidine.

Helicobacter antigen(s) may be delivered in accordance with thisinvention in ISCOMS (immune stimulating complexes), ISCOMS containingCTB, liposomes or encapsulated in compounds such as acrylates orpoly(DL-lactide-co-glycoside) to form microspheres of a size suited toadsorption by M cells. Alternatively, micro or nanoparticles may becovalently attached to molecules such as vitamin B12 which have specificgut receptors. Antigen(s) may also be incorporated into oily emulsionsand delivered orally. An extensive though not exhaustive list ofadjuvants can be found in Cox and Coulter, 1992.

Other adjuvants, as well as conventional pharmaceutically acceptablecarriers, excipients, buffers or diluents, may also be included in thetherapeutic vaccine composition of this invention. The vaccinecomposition may, for example, be formulated in enteric coated gelatinecapsules including sodium bicarbonate buffers together with theHelicobacter antigen(s) and mucosal adjuvant.

Generally, a vaccine composition in accordance with the presentinvention will comprise an immunologically effective amount ofHelicobacter antigen(s), and optionally a mucosal adjuvant, inconjunction with one or more conventional pharmaceutically acceptablecarriers and/or diluents. As used herein "pharmaceutically acceptablecarriers and/or diluents" include any and all solvents, dispersionmedia, aqueous solutions, coatings, antibacterial and antifungal agents,isotonic and absorption delaying agents and the like. The use of suchmedia and agents for pharmaceutical active substances is well known inthe art and is described by way of example in Remington's PharmaceuticalSciences, 18th Edition, 1990, Mack Publishing Company, Pennsylvania,U.S.A.

The pharmaceutical composition of this invention may be orallyadministered directly to the mammalian host, for example, with an inertdiluent or with an assimilable edible carrier, or it may be enclosed inhard or soft shell gelatine capsule, or it may be compressed intotablets, or it may be incorporated directly with the solid or liquidfood of the diet. For oral therapeutic administration, the activecompound may be incorporated with excipients and used in the form ofingestible tablets, buccal tablets, troches, capsules, elixirs,suspensions, syrups, wafers, and the like. The percentage of activecomponent in the compositions and preparations may of course be variedand is such that a suitable dosage will be obtained to beimmunologically effective.

Solid oral dosage units such as tablets, troches, pills, capsules andthe like may also contain the following: a binder such as gumtragacanth, acacia, corn starch or gelatin; excipients such as dicalciumphosphate; a disintegrating agent such as corn starch, potato starch,alginic acid and the like; a lubricant such as magnesium stearate; and asweetening agent such as sucrose, lactose or saccharin may be added or aflavouring agent such as peppermint, oil of wintergreen, or cherryflavouring. When the dosage unit form is a capsule, it may contain, inaddition to materials of the above type, a liquid carrier. Various othermaterials may be present as coatings or to otherwise modify the physicalform of the dosage unit. For instance, tablets, pills or capsules may becoated with shellac, sugar or both. A syrup or elixir may contain theactive component, sucrose as a sweetening agent, methyl andprophylparabens as preservatives, a dye and flavouring such as cherry ororange flavour. Of course, any material used in preparing any dosageunit form should be pharmaceutically pure and substantially non-toxic inthe amounts employed.

The vaccine composition of the invention is administered orally inamounts readily determined by persons of ordinary skill in this art.Thus, for adults a suitable dosage would be in the range of 10 μg to 10g, for example 50 μg to 3 g. Similar dosage ranges would be applicablefor children.

As noted above, a suitable mucosal adjuvant is cholera toxin. The amountof mucosal adjuvant employed depends on the type of mucosal adjuvantused. For example, when the mucosal adjuvant is cholera toxin, it issuitably used in an amount of 10 nanogram to 50 μg, for example 01 μg to10 μg. When the mucosal adjuvant is E. coli heat labile toxin, suitableamounts are 1 μg to 1 mg, for example 5 μg to 50 μg.

In work leading to the present invention, active immunisation of micepreviously infected with H. felis, with oral doses of cholera toxin orE. coli HLT adjuvant and a whole cell H. felis or H. pylori sonicate,result in the clearance of H. felis from the gastric mucosa. It istherefore anticipated that active immunisation of infected humans withoral doses of a mucosal adjuvant with H. pylori antigen(s) will resultin the clearance of H. pylori from the gastric mucosa. Based on previousstudies with this model using anti-H. pylori agents, it is consideredthat this is the first evidence of the therapeutic potential of activeimmunisation with H. pylori vaccines, and indicates that a vaccinecomposition for the therapy of human H. pylori-associated gastroduodenaldisease is a preparation of Helicobacter antigen(s), optionally andpreferably combined with a mucosal adjuvant.

It will be apparent to persons skilled in the field that effectivetreatment of Helicobacter pylori infection in humans with an oralvaccine composition of Helicobacter antigen(s) which will eradicate orsuppress the infection will provide a significant therapeutic benefitvia the suppression or elimination of gastritis, prevention of pepticulcer relapse and reduction in the harmful sequelae of Helicobacterpylori infection including peptic ulceration and gastric cancer.

The present invention is further illustrated in the following,non-limiting Examples.

EXAMPLE 1

One hundred and sixty female SPF mice from the Animal Breeding Unit ofthe University of New South Wales, Australia, were infected with fouroral doses of 10⁹ -10¹⁰ living Helicobacter felis (ATCC culture 49179)given two days apart.

Bacteria were grown in plastic Petri dishes on Blood Agar Base No. 2,3.8% w/v (Oxoid, Basingstoke, U.K.) with 7% v/v whole horse blood(Oxoid), containing amphotericin B (Fungizone, Squibb, Princeton, N.J.,USA) 2.5 mg/l; trimethoprim (Sigma, St.Louis, Mo., USA), 10 mg/l. Plateswere incubated in a microaerophilic humid atmosphere (Oxoid, BR56) at37° C. for 48 hours.

Sonicates were prepared by growth of the organisms, as described above,followed by harvesting of the organisms in 0.1 molar phosphate bufferedsaline (PBS). The cells were washed, collected by centrifugation, washedonce in PBS, and resuspended in fresh PBS. The cells were then sonicatedat the rate of one minute per ml of cell suspension (50% duty cycle)using a B-30 Branson Cell Disrupter. The sonicate was stored at -20° C.

On days 28, 42, 44 and 47 after administration of the last infectingdose of H. felis, 20 of the mice were given orally 0.2 ml of asuspension containing 10 μg of cholera toxin (Sigma C 3012) and asonicate of H. felis containing 1 mg protein (BIO-RAD DC protein assay).

Samples of antral mucosa were tested for infection using a rapidmicrotitre urease test as described previously (Lee et al., 1990). Thistest has been validated as being highly predictive of H. felis gastricinfection. Groups of 40 mice (20 vaccinates and 20 controls) wereeuthanased at intervals of 1 week, 1 month, 2 months and 3 months afterthe last dose of vaccine.

The results are shown in Table 1.

These results show that treatment of H. felis infected mice with an oralvaccine comprised of Helicobacter antigens and a mucosal adjuvant,results in cure of the infection in a significant proportion of mice.This effect is evident 1 week after cessation of therapy, and continuesfor at least 3 months, demonstrating that the mice have been cured oftheir infection.

                  TABLE 1    ______________________________________            Proportion of H. felis infected mice    Immunisation              1 week    1 month   2 months                                         3 months    ______________________________________    Nil       19/19     20/20     18/19  13/19    Sonicate plus CT               2/20      3/20      6/20   1/17              P < 0.0001*                        P < 0.0001                                  P < 0.05                                         P < 0.0001    ______________________________________     *Fisher's exact test (two tailed).

EXAMPLE 2

One hundred female BALB/c mice from the Animal Breeding Unit of theUniversity of New South Wales, Australia, were infected with 3 oraldoses of 10⁸ living Helicobacter felis (ATCC culture 49179) given 2 daysapart, i.e. days 1, 3 and 5.

Bacteria were grown in plastic Petri dishes on Blood Agar Base No. 2,3.8% w/v (Oxoid, Basingstoke, U.K.) with 7% v/v whole horse blood),(Oxoid), containing amphotericin B (Fungizone, Squibb, Princeton, N.J.,USA) 2.5 mg/l; trimethoprim (Sigma, St.Louis, Mo., USA), 10 mg/l. Plateswere incubated in a microaerophilic humid atmosphere (Oxoid, BR56) at37° C. for 48 hours.

Sonicates were prepared by growth of the organisms, as described above,followed by harvesting of the organisms in 0.1 molar phosphate bufferedsaline (PBS). The cells were washed collected by centrifugation, washedonce in PBS, and resuspended in fresh PBS. The cells were then sonicatedat the rate of one per minute per ml of cell suspension (50% duty cycle)using a B-30 Branson Cell Disrupter. The sonicate was stored at -20° C.

On days 21, 35, 37, and 40 after administration of the last infectingdose of H. felis, 20 mice were each given orally 0.2 ml of a solutioncontaining 10 μg of cholera toxin (Sigma C 3012), 20 mice were eachgiven orally 0.2 ml of a suspension containing 10 μg of cholera toxinand a sonicate of H. felis containing 1 mg protein (BIO-RAD DC proteinassay), 20 mice were each given orally 0.2 ml of a suspension containinga sonicate of H. felis containing 1 mg protein, 20 mice were each givenorally 0.2 ml of a suspension containing 10 μg of cholera toxin and asonicate of H. pylori (strain 921023) containing 1 mg protein, and 20mice were not orally vaccinated.

One week after the final immunising dose all the mice were euthanased.Samples of antral mucosa were tested for infection using a rapidmicrotitre urease test as described previously (Lee et al., 1990). Thistest has been validated as being highly predictive of H. felis gastricinfection.

The results are shown in Table 2.

These results show that oral administration of Helicobacter antigensderived from either H. felis, or H. pylori along with a mucosaladjuvant, will cure a significant portion of H. felis infected mice.

                  TABLE 2    ______________________________________                  Number of animals    Vaccine       infected        Significance    ______________________________________    Nil           16/20    CT alone      15/20           N.S.    H. felis sonicate alone                  12/20           N.S.    H. felis sonicate plus CT                   8/19           P < 0.05*    H. pylori sonicate plus CT                   4/20           P < 0.001    ______________________________________     *Fisher's exact test (two tailed)

EXAMPLE 3

One hundred female SPF mice from the Animal Breeding Unit of theUniversity of New South Wales, Australia, were infected with 4 oraldoses of 10⁹ -10¹⁰ living Helicobacter felis (ATCC culture 49179) given2 days apart. 20 female SPF mice were left uninfected, as negativecontrols.

Bacteria were grown in plastic Petri dishes on Blood Agar Base No. 2,3.8% w/v (Oxoid, Basingstoke, UK) with 7% v/v whole horse blood (Oxoid),containing amphotericin B (Fungizone, Squibb, Princeton, N.J., USA) 2.5mg/l; trimethoprim (Sigma, St.Louis, Mo., USA), 10 mg/l. Plates wereincubated in a microaerophilic humid atmosphere (Oxoid, BR56) at 37° C.for 48 hours.

Sonicates were prepared by growth of the organisms, as described above,followed by harvesting of the organisms in 0.1 molar phosphate bufferedsaline (PBS). The cells were washed, collected by centrifugation, washedonce in PBS, and resuspended in fresh PBS. The cells were then sonicatedat the rate of one per minute per ml of cell suspension (50% duty cycle)using a B-30 Branson Cell Disrupter. The sonicate was stored at -20° C.

Starting between 6 weeks and 9 weeks after their last infecting dose ofH. felis, 20 mice were each given orally 0.2 ml of a solution containing25 μg of E. coli heat labile toxin (HLT) (Sigma E 8015), 20 mice wereeach given orally 0.2 ml of a suspension containing 25 μg of HLT and asonicate of H. pylori containing 1 mg protein (BIO-RAD DC proteinassay), 20 mice were each given orally 0.2 ml of a suspension containinga sonicate of H. pylori containing 1 mg protein, and 40 mice were notorally vaccinated.

Each group received three further doses 15, 17 and 20 days after theirinitial dose.

Four weeks after the final immunising dose all the mice were euthanased.Samples of antral mucosa were tested for infection using a rapidmicrotitre urease test as described previously (Lee et al., 1990). Thistest has been validated as being highly predictive of H. felis gastricinfection.

The results are shown in Table 3.

They show that oral administration of Helicobacter antigens derived fromH. pylori along with a mucosal adjuvant E. coli heat labile toxin, willcure a significant portion of H. felis infected mice.

                  TABLE 3    ______________________________________                      Proportion of H. felis    Treatment Group   infected mice.    ______________________________________    Uninfected, unvaccinated                       0/20    Infected, unvaccinated                      40/40    Infected, Hp antigen alone                      20/20    Infected, E. coli HLT alone                      20/20    Infected, Hp antigen & HLT                       6/19*    ______________________________________     *P < 0.0001 (Fisher's exact test, two tailed).

REFERENCES

Blaser, M. J. (1992). Helicobacter pylori: Its role in disease. Clin.Infect. Dis. 15, 386-393.

Burke, D. S. (1993). Of postulates and peccadilloes: Robert Koch andvaccine (tuberculin) therapy for tuberculosis. Vaccine, 11, 795-804.

Cox, J. and Coulter, A. (1992). Advances in Adjuvant Technology andApplication. In Animal Parasite Control Utilising Biotechnology. EditedW. K. Yong, CRC Press.

Czinn, S. J., Cai, A. and Nedrud, J. G. (1993). Protection of germ-freemice from infection by Helicobacter felis after active oral or passiveIgA immunization. Vaccine,11, 637-642.

Dick-Hegedus, E. and Lee, A. (1991). Use of a mouse model to examineanti-Helicobacter pylori agents. Scand. J. Gastrolenterol. 26, 909-915.

Goodwin, C. S. (1993). Overview of Helicobacter pylori gastritis, pepticulcer, and gastric cancer and the possible development of an H. pylorivaccine. In Helicobacter pylori Biology and Clinical Practice. Edited byGoodwin and Worsley. CRC Press.

Lee, A., Fox, J. G., Otto, G. and Murphy, J. (1990). A small animalmodel of human Helicobacter pylori active chronic gastritis.Gastroenterology, 99, 1316-1323.

O'Connor, H. J. 91992). Eradication of Helicobacter pylori: Therapiesand clinical implications. Postgrad. Med. J. 68, 549-557.

Parsonnet, J., Friedman, G. D., Vandersteen, D. P., Chang, Y., Vogelman,H. J., Orentreich, N. and Sibley, R. K. (1991). Helicobacter pyloriinfection and the risk of gastric carcinoma. N. Engl. J. Med. 325,1127-1131.

Varga, L., Locsei, Z., Dobronte, Z., Lakatos, F., Brozik, M. andMeretey, K. (1992). Helicobacter pylori allergy. Orv. Hetil. 133,359-361.

We claim:
 1. A method for the treatment of a pre-existing Helicobacterinfection in a mammalian host, which comprises mucosal administration tothe infected host of (a) an immunologically effective amount of one ormore Helicobacter antigens, in association with (b) a mucosal adjuvant,wherein said administration of (a) in association with (b) eradicates orsuppresses the pre-existing infection in the host.
 2. A method accordingto claim 1, wherein said one or more Helicobacter antigens comprise oneor more H. pylori antigens.
 3. A method according to claim 1, whereinsaid one or more Helicobacter antigens comprise one or more H. felisantigens.
 4. A method according to claim 1, wherein said one or moreHelicobacter antigens are provided by a sonicate of Helicobacter cells.5. A method according to claim 1, wherein said adjuvant is cholera toxinor E. coli heat labile toxin.
 6. A method according to claim 1, whereinsaid infected host is an infected human.
 7. A method according to claim1, wherein the mucosal adjuvant has mucosal delivery activity.
 8. Amethod according to claim 1, further comprising the step of detecting atherapeutic effect in said infected host.
 9. A method according to claim1, further comprising administration of an antibiotic to the infectedhost.
 10. A method for the treatment of a pre-existing Helicobacterinfection in a mammalian host, which comprises oral administration tothe infected host of (a) an immunologically effective amount of one ormore Helicobacter antigens, in association with (b) a mucosal adjuvant,wherein said administration of (a) in association with (b) eradicates orsuppresses the pre-existing infection in the host.
 11. A methodaccording to claim 10, wherein said one or more Helicobacter antigenscomprise one or more H. pylori antigens.
 12. A method according to claim10, wherein said one or more Helicobacter antigens comprise one or moreH. felis antigens.
 13. A method according to claim 10, wherein said oneor more Helicobacter antigens are provided by a sonicate of Helicobactercells.
 14. A method according to claim 10, wherein said adjuvant ischolera toxin or E. coli heat labile toxin.
 15. A method according toclaim 10, wherein said infected host is an infected human.
 16. A methodaccording to claim 10, wherein the mucosal adjuvant has mucosal deliveryactivity.
 17. A method according to claim 10, further comprising thestep of detecting a therapeutic effect in said infected host.
 18. Amethod according to claim 10, further comprising administration of anantibiotic to the infected host.
 19. A method according to claim 11,wherein said one or more Helicobacter antigens is selected from thegroup consisting of H. pylori urease, H. pylori cytotoxin, H. pyloricytotoxin associated immunodominant antigen, and H. pylori heat shockprotein.
 20. A method according to claim 10, wherein said one or moreHelicobacter antigens is selected from the group consisting of H. pyloriurease, H. pylori cytotoxin, H. pylori cytotoxin associatedimmunodominant antigen, and H. pylori heat shock protein.